SNPMiner Trials by Shray Alag


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Report for Mutation G11778A

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 12 clinical trials

Clinical Trials


1 A Double-Blind, Randomised, Placebo-Controlled Study of the Efficacy, Safety and Tolerability of Idebenone in the Treatment of Patients With Leber's Hereditary Optic Neuropathy

This study is meant to assess the effectiveness of idebenone on visual function measures in patients with Leber's Hereditary Optic Neuropathy over a 6 months period.

NCT00747487 Leber's Hereditary Optic Neuropathy Drug: Idebenone Drug: Placebo
MeSH: Peripheral Nervous System Diseases Optic Nerve Diseases Optic Atrophy, Hereditary, Leber
HPO: Abnormal peripheral nervous system morphology Leber optic atrophy Peripheral neuropathy Polyneuropathy

Inclusion Criteria: - Age > or = 14 years and < 65 years - Impaired visual acuity in at least one eye due to LHON - Onset of visual loss due to LHON lies five years or less prior to Baseline - Confirmation of either G11778A, T14484C or G3460A LHON mtDNA mutations at >60% in blood - No explanation for the visual failure besides LHON - Body weight ≥ 45 kg - Negative urine pregnancy test at Screening and at Baseline (women of childbearing potential). --- G11778A ---

Exclusion Criteria: - Treatment with Coenzyme Q10 or idebenone within 1 month prior to Baseline - Pregnancy and/or breast-feeding - Weekly alcohol intake 35 units (men) or 24 units (women) - Current drug abuse - Clinically significant abnormalities of clinical haematology or biochemistry including, but not limited to, elevations greater than 2 times the upper limit of normal of AST, ALT or creatinine - Participation in another clinical trial of any investigational drug within 3 months prior to Baseline - Other factor that, in the investigator's opinion, excludes the patient from entering the study Inclusion Criteria: - Age > or = 14 years and < 65 years - Impaired visual acuity in at least one eye due to LHON - Onset of visual loss due to LHON lies five years or less prior to Baseline - Confirmation of either G11778A, T14484C or G3460A LHON mtDNA mutations at >60% in blood - No explanation for the visual failure besides LHON - Body weight ≥ 45 kg - Negative urine pregnancy test at Screening and at Baseline (women of childbearing potential). --- G11778A ---

Primary Outcomes

Measure: Best recovery of logMAR visual acuity between baseline and Week 24 in either right or left eye

Time: 24 weeks

Secondary Outcomes

Measure: Change in the patient's best logMAR visual acuity between baseline and week 24

Time: 24 weeks

Measure: Change in scotoma area in both eyes

Time: Day -1, Week 4, Week 12, Week 24

Measure: Change in optic nerve fibre layer thickness in both eyes

Time: Day -1, Week 4, Week 12, Week 24

Measure: Colour contrast sensitivity in both eyes (in a subset of patients)

Time: Day -1, Week 4, Week 12, Week 24

Measure: logMAR visual acuity as a continuous variable in both eyes

Time: Screening, Day -1, Week 4, Week 12, Week 24, Week 28

Measure: Clinical Global Impression of Change

Time: Week 4, Week 12 and Week 24

Measure: Change in Health-Related Quality of Life (HRQOL)

Time: Day -1, Week 4, Week 12, Week 24

Measure: Change in self-reported general energy levels

Time: Day -1, Week 4, Week 12, Week 24, Week 28

Measure: Proportion of patients in which visual acuity in the initially least affected eye does not deteriorate to 1.0 log MAR or more ( in LHON patients with eye still less affected than 0.5 logMAR at trial entry)

Time: 24 weeks

Measure: Plasma levels of idebenone matched to measures of efficacy and safety

Time: 24 weeks

Measure: • Best visual acuity at Week 24 (best eye at Week 24) compared to best visual acuity at Baseline (best eye at Baseline)

Time: 24 weeks

Measure: • Count of eyes/ patients for which the visual acuity improves between baseline and week 24

Time: 24 weeks

2 An Open Label Dose Escalation Clinical Trial to Evaluate the Safety and the Tolerability of GS010 (rAAV2/2-ND4) in Patients With Leber Hereditary Optic Neuropathy Due to Mutations in the Mitochondrial NADH Dehydrogenase 4 Gene

The purpose of this study is to evaluate the safety and tolerability profile of ascending doses of GS010 in Leber Hereditary Optic Neuropathy (LHON) patients.

NCT02064569 Leber Hereditary Optic Neuropathy Genetic: GS010
MeSH: Optic Nerve Diseases Optic Atrophy, Hereditary, Leber
HPO: Leber optic atrophy

Inclusion Criteria: Documented diagnosis of LHON based on a genetic test confirming the presence of the G11778A mutation in the mitochondrial ND4 Age 18 years old or older at the time of study entry (informed consent signature) Visual acuity ≤ 1/10 of the less functional eye Exclusion Criteria: Any known allergy or hypersensibility to one of the product used during the trial Contraindication to IVT surgery (anaemia Hb <8g/dl, severe cardiovascular disease, severe coagulopathy…) Disorder of the ocular humors and of the internal retina involving visual disability Glaucoma Presence of other pathology whose symptoms or associated treatments might affect the retina or the optic nerve Vascular retinal occlusion Narrow angle contra-indicating pupillary dilation Other cause of optic neuropathy (inflammatory conditions or exposure to toxins...) Patients presenting known mutation of other genes implicated in pathological retinal conditions Inclusion Criteria: Documented diagnosis of LHON based on a genetic test confirming the presence of the G11778A mutation in the mitochondrial ND4 Age 18 years old or older at the time of study entry (informed consent signature) Visual acuity ≤ 1/10 of the less functional eye Exclusion Criteria: Any known allergy or hypersensibility to one of the product used during the trial Contraindication to IVT surgery (anaemia Hb <8g/dl, severe cardiovascular disease, severe coagulopathy…) Disorder of the ocular humors and of the internal retina involving visual disability Glaucoma Presence of other pathology whose symptoms or associated treatments might affect the retina or the optic nerve Vascular retinal occlusion Narrow angle contra-indicating pupillary dilation Other cause of optic neuropathy (inflammatory conditions or exposure to toxins...) Patients presenting known mutation of other genes implicated in pathological retinal conditions Leber Hereditary Optic Neuropathy Optic Nerve Diseases Optic Atrophy, Hereditary, Leber null --- G11778A ---

Inclusion Criteria: Documented diagnosis of LHON based on a genetic test confirming the presence of the G11778A mutation in the mitochondrial ND4 Age 18 years old or older at the time of study entry (informed consent signature) Visual acuity ≤ 1/10 of the less functional eye Exclusion Criteria: Any known allergy or hypersensibility to one of the product used during the trial Contraindication to IVT surgery (anaemia Hb <8g/dl, severe cardiovascular disease, severe coagulopathy…) Disorder of the ocular humors and of the internal retina involving visual disability Glaucoma Presence of other pathology whose symptoms or associated treatments might affect the retina or the optic nerve Vascular retinal occlusion Narrow angle contra-indicating pupillary dilation Other cause of optic neuropathy (inflammatory conditions or exposure to toxins...) Patients presenting known mutation of other genes implicated in pathological retinal conditions Inclusion Criteria: Documented diagnosis of LHON based on a genetic test confirming the presence of the G11778A mutation in the mitochondrial ND4 Age 18 years old or older at the time of study entry (informed consent signature) Visual acuity ≤ 1/10 of the less functional eye Exclusion Criteria: Any known allergy or hypersensibility to one of the product used during the trial Contraindication to IVT surgery (anaemia Hb <8g/dl, severe cardiovascular disease, severe coagulopathy…) Disorder of the ocular humors and of the internal retina involving visual disability Glaucoma Presence of other pathology whose symptoms or associated treatments might affect the retina or the optic nerve Vascular retinal occlusion Narrow angle contra-indicating pupillary dilation Other cause of optic neuropathy (inflammatory conditions or exposure to toxins...) Patients presenting known mutation of other genes implicated in pathological retinal conditions Leber Hereditary Optic Neuropathy Optic Nerve Diseases Optic Atrophy, Hereditary, Leber null --- G11778A --- --- G11778A ---

Primary Outcomes

Measure: Incidence of local and general adverse events and Serious Adverse Events

Time: Up to 48 weeks

3 An Open-label Dose Escalation Study of an Adeno-associated Virus Vector (scAAV2-P1ND4v2) for Gene Therapy of Leber's Hereditary Optic Neuropathy (LHON) Caused by the G11778A Mutation in Mitochondrial DNA

Hypotheses: The primary hypothesis being tested is that there will be no toxicity resulting in loss of vision to no light perception in injected eyes.

NCT02161380 Leber's Hereditary Optic Neuropathy Drug: injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low), Drug: injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med) Drug: injection of scAAV2-P1ND4v2 2.4 X10e10vg (High) Drug: injection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher)
MeSH: Optic Nerve Diseases Optic Atrophy, Hereditary, Leber
HPO: Leber optic atrophy

An Open-label Dose Escalation Study of an Adeno-associated Virus Vector (scAAV2-P1ND4v2) for Gene Therapy of Leber's Hereditary Optic Neuropathy (LHON) Caused by the G11778A Mutation in Mitochondrial DNA. --- G11778A ---

Inclusion Criteria: 1. Age 15 or older; 2. Patients with LHON and the G11778A mitochondrial DNA mutation. --- G11778A ---

A previous CLIA certified genetic lab result showing the LHON G11778A mutation will be accepted for inclusion; 3. Ability to perform tests of visual and retinal function; 4. Ability to comply with research procedures; 5. Able and willing to provide informed consent before undergoing any study related procedures. --- G11778A ---

Primary Outcomes

Description: Incidence of local and general adverse events and Serious Adverse Events

Measure: Assessment of Primary Endpoint - Toxicity

Time: 1 year

4 A Randomized, Double-Masked, Sham-Controlled Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 in Subjects Affected for 6 Months or Less by LHON Due to the G11778A Mutation in the Mitochondrial ND4 Gene

The goal of this clinical trial is to assess the effectiveness of GS010, a gene therapy, in improving the visual outcome in participants with Leber Hereditary Optic Neuropathy (LHON) due to the G11778A ND4 mitochondrial mutation when vision loss is present for six months or less.

NCT02652767 Optic, Atrophy, Hereditary, Leber Biological: GS010 Device: Sham Intravitreal Injection
MeSH: Atrophy

A Randomized, Double-Masked, Sham-Controlled Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 in Subjects Affected for 6 Months or Less by LHON Due to the G11778A Mutation in the Mitochondrial ND4 Gene. --- G11778A ---

Efficacy Study of GS010 for the Treatment of Vision Loss up to 6 Months From Onset in LHON Due to the ND4 Mutation The goal of this clinical trial is to assess the effectiveness of GS010, a gene therapy, in improving the visual outcome in participants with Leber Hereditary Optic Neuropathy (LHON) due to the G11778A ND4 mitochondrial mutation when vision loss is present for six months or less. --- G11778A ---

Inclusion Criteria: Participants included in the study must satisfy all the following criteria at the Inclusion Visit (Visit 2). 1. Documented results of genotyping showing the presence of the G11778A mutation in the ND4 gene and the absence of the other primary Leber Hereditary Optical Neuropathy (LHON)-associated mutations (ND1 or ND6) in the participant's mitochondrial DNA. 2. Review of all selection criteria to ensure continued compliance. --- G11778A ---

Primary Outcomes

Description: Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Visual acuity is measured in "logarithm of the minimal angle of resolution" (LogMAR), which was derived from the number of letters participants could read on the ETDRS chart. 1 ETDRS line = 5 letters 1 ETDRS line = 0.1 LogMAR A lower LogMAR score denotes better visual acuity. A positive change from baseline indicates a worsening in symptoms. Change = (Week 48 score - Baseline score).

Measure: Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 48

Time: Baseline and Week 48

Secondary Outcomes

Description: Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Visual acuity is measured in "logarithm of the minimal angle of resolution" (LogMAR), which was derived from the number of letters participants could read on the ETDRS chart. 1 ETDRS line = 5 letters 1 ETDRS line = 0.1 LogMAR A lower LogMAR score denotes better visual acuity. A positive change from baseline indicates a worsening in symptoms. Change = (Week 72 score - Baseline score) or (Week 96 score - Baseline score). Missing data was imputed by the linear interpolation method.

Measure: Change From Baseline in ETDRS Visual Acuity (Quantitative Score)

Time: Baseline; Week 72 and Week 96

Description: An eye was determined as a responder to treatment based on 2 different definitions. Definition 1: An eye responder was defined by an improvement of the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity score of at least 15 letters compared to Baseline, or a final visual acuity greater than a Snellen acuity equivalent of 20/200 (a score of at least 1 letter). Definition 2: An eye responder was defined by an improvement of the ETDRS score of at least 20 letters compared to Baseline.

Measure: Number of Eye Responders to Treatment

Time: Baseline; Week 48; Week 72 and Week 96

Description: A subject responder was defined as a participant whose Early Treatment Diabetic Retinopathy Study (ETDRS) score of the treated eye (that received GS010), was at least 15 letters better than the sham eye, or whose treated eye had a "logarithm of the minimal angle of resolution" (LogMAR) acuity score of at least 0.3 LogMAR better than the sham eye. For the Week 96 analysis, if no score was available for Week 96, the score from the previous visit was used.

Measure: Number of Subject Responders to Treatment

Time: Week 48; Week 72 and Week 96

Description: Ganglion cell layer (GCL) macular volume was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).

Measure: Change From Baseline in GCL Macular Volume

Time: Baseline; Week 48; Week 72 and Week 96

Description: Retinal nerve fiber layer (RNFL) temporal quadrant thickness was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).

Measure: Change From Baseline in RNFL Temporal Quadrant Thickness

Time: Baseline; Week 48; Week 72 and Week 96

Description: Papillomacular bundle thickness was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).

Measure: Change From Baseline in RNFL Papillomacular Bundle Thickness

Time: Baseline; Week 48; Week 72 and Week 96

Description: Early Treatment Diabetic Retinopathy Study (ETDRS) total macular volume was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).

Measure: Change From Baseline in ETDRS Total Macular Volume

Time: Baseline; Week 48; Week 72 and Week 96

Description: The assessment of standardized automated visual fields was measured using the Humphrey Visual Field (HVF) Analyzer II. Automated visual fields included the assessment of foveal threshold sensitivities. Foveal threshold sensitivity is measured in decibels (dB), which ranges from 0 dB to 50 dB. A sensitivity threshold of 0 dB indicates not being able to see the most intense perimetric stimulus, while higher dB indicates better/normal foveal vision. A positive change from baseline indicates an improvement of symptoms.

Measure: Change From Baseline in the Foveal Threshold Sensitivities Obtained With HVF Analyzer II

Time: Baseline; Week 48; Week 72 and Week 96

Description: The assessment of standardized automated visual fields was measured using the Humphrey Visual Field (HVF) Analyzer II. Automated visual fields included the assessment of the mean deviation (MD) in decibels (dB) of sensitivity.

Measure: Visual Field Mean Deviation in Decibels of Sensitivity Obtained With HVF Analyzer II

Time: Baseline; Week 48; Week 72 and Week 96

Description: The assessment of contrast sensitivity was measured using the Pelli-Robson chart. The chart uses letters arranged in groups whose contrast varies from high to low. Participants read the letters, starting with the highest contrast, until they are unable to read 2 or 3 letters in a single group. Each eye is assigned a score based on the contrast of the last group in which 2 or 3 letters were correctly read, ranging from 0 to 2.2 "log of contrast sensitivity" (LogCS) units. A score of 2.0 LogCS, represents a normal sensitivity contrast, and indicates the eye was able to detect 2 of the 3 letters with a contrast of 1 percent (contrast sensitivity = 100 percent or log 2). Scores less than 2.0 signify poorer contrast sensitivity. Pelli-Robson contrast sensitivity score of less than 1.5 is consistent with visual impairment and a score of less than 1.0 represents in visual disability. A negative change from baseline indicates worsening in symptoms.

Measure: Change From Baseline in Contrast Sensitivity

Time: Baseline; Week 48; Week 72 and Week 96

Description: The assessment of color vision was measured using the Farnsworth-Munsell 100-Hue Color Test. Each of the 4 trays consisted of 21 caps. Participants were asked to sort the randomly arranged caps following the hue order from the first to the last fixed caps. The total error score (TES) was derived by the frequency the caps were misplaced and the severity, or distance of the misplacement. Errors were made whenever caps were misplaced from the correct order. Error scores were calculated according to the distance between any two caps. The error score for each individual cap was the sum of the difference between the number of that cap and the numbers of the cap adjacent to it, minus 2. TES was the total sum of the error scores of the entire set of caps. The best possible score was 0 and there is no defined upper limit to the total error score range. A lower score indicates improved color discrimination ability. A positive change from baseline indicates a worsening in symptoms.

Measure: Change From Baseline in Color Vision

Time: Baseline; Week 48 and Week 96

5 Randomized, Double-Masked, Sham-Controlled Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 in Subjects Affected for More Than 6 Months and To 12 Months by LHON Due to the G11778A Mutation in the ND4 Gene

The goal of this clinical trial is to assess the effectiveness of GS010, a gene therapy, in improving the visual outcome in participants with Leber Hereditary Optic Neuropathy (LHON) due to the G11778A ND4 mitochondrial mutation when vision loss is present for more than six months and up to one year.

NCT02652780 Optic, Atrophy, Hereditary, Leber Biological: GS010 Device: Sham Intravitreal Injection
MeSH: Atrophy

Randomized, Double-Masked, Sham-Controlled Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 in Subjects Affected for More Than 6 Months and To 12 Months by LHON Due to the G11778A Mutation in the ND4 Gene. --- G11778A ---

Efficacy Study of GS010 for Treatment of Vision Loss From 7 Months to 1 Year From Onset in LHON Due to the ND4 Mutation (REVERSE) The goal of this clinical trial is to assess the effectiveness of GS010, a gene therapy, in improving the visual outcome in participants with Leber Hereditary Optic Neuropathy (LHON) due to the G11778A ND4 mitochondrial mutation when vision loss is present for more than six months and up to one year. --- G11778A ---

Inclusion Criteria: Participants included in the study must satisfy all the following criteria at the Inclusion Visit (Visit 2). 1. Documented results of genotyping showing the presence of the G11778A mutation in the ND4 gene and the absence of the other primary LHON-associated mutations (ND1 or ND6) in the participant's mitochondrial DNA. 2. Review of all selection criteria to ensure continued compliance. --- G11778A ---

Primary Outcomes

Description: Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The visual acuity logarithm of the minimal angle of resolution (LogMAR) score was derived from the number of letters participants could read on the ETDRS chart. 1 ETDRS line = 5 letters 1 ETDRS line = 0.1 LogMAR A lower LogMAR score denotes better visual acuity and a negative change from baseline indicates an improvement in visual acuity. Change = (Week 48 score - Baseline score).

Measure: Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 48

Time: Baseline and Week 48

Secondary Outcomes

Description: Visual acuity was derived from the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The visual acuity logarithm of the minimal angle of resolution (LogMAR) score was derived from the number of letters participants could read on the ETDRS chart. 1 ETDRS line = 5 letters 1 ETDRS line = 0.1 LogMAR A lower LogMAR score denotes better visual acuity and a negative change from baseline indicates an improvement in visual acuity. Change = (Week 96 score - Baseline score).

Measure: Change From Baseline in ETDRS Visual Acuity (Quantitative Score) at Week 96

Time: Baseline and Week 96

Description: An eye was determined as a responder to treatment based on 2 different definitions. Definition 1: An eye responder was defined by an improvement of the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity score of at least 15 letters compared to Baseline, or a final visual acuity greater than a Snellen acuity equivalent of 20/200 (a score of at least 1 letter). Definition 2: An eye responder was defined by an improvement of the ETDRS score of at least 20 letters compared to Baseline.

Measure: Number of Eye Responders to Treatment at Week 48 and Week 96

Time: Baseline; Week 48 and Week 96

Description: A subject responder was defined as a participant whose Early Treatment Diabetic Retinopathy Study (ETDRS) score of the treated eye (that received GS010), was at least 15 letters better than the sham eye, or whose treated eye had a logarithm of the minimal angle of resolution (logMAR) acuity score of at least 0.3 logMAR better than the sham eye.

Measure: Number of Subject Responders to Treatment at Week 48 and Week 96

Time: Week 48 and Week 96

Description: Ganglion cell layer (GCL) macular volume was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).

Measure: Change From Baseline in GCL Macular Volume at Week 48 and Week 96

Time: Baseline and Week 48; Baseline and Week 96

Description: Retinal nerve fiber layer (RNFL) temporal quadrant thickness was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).

Measure: Change From Baseline in RNFL Temporal Quadrant Thickness at Week 48 and Week 96

Time: Baseline and Week 48; Baseline and Week 96

Description: Papillomacular bundle thickness was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).

Measure: Change From Baseline in Papillomacular Bundle Thickness at Week 48 and Week 96

Time: Baseline and Week 48; Baseline and Week 96

Description: Early Treatment Diabetic Retinopathy Study (ETDRS) total macular volume was measured as a parameter of spectral domain-optical coherence tomography (SD-OCT). SD-OCT was obtained with the Spectralis® OCT (Heidelberg Engineering).

Measure: Change From Baseline in ETDRS Total Macular Volume at Week 48 and Week 96

Time: Baseline and Week 48; Baseline and Week 96

Description: The assessment of standardized automated visual fields was measured using the Humphrey Visual Field (HVF) Analyzer II. Automated visual fields included the assessment of foveal threshold sensitivities. Foveal threshold sensitivity is measured in decibels (dB), which ranges from 0 dB to 50 dB. A sensitivity threshold of 0 dB indicates not being able to see the most intense perimetric stimulus, while higher dB indicates better/normal foveal vision. A positive change from baseline indicates an improvement of symptoms.

Measure: Change From Baseline in the Foveal Threshold Sensitivities Obtained With HVF Analyzer II at Week 48 and Week 96

Time: Baseline and Week 48; Baseline and Week 96

Description: The assessment of standardized automated visual fields was measured using the Humphrey Visual Field (HVF) Analyzer II. Automated visual fields included the assessment of the mean deviation (MD) in decibels (dB) of sensitivity.

Measure: Visual Field Mean Deviation in Decibels of Sensitivity Obtained With HVF Analyzer II at Week 48 and Week 96

Time: Baseline, Week 48 and Week 96

Description: The assessment of contrast sensitivity was measured using the Pelli-Robson chart. The chart uses letters arranged in groups whose contrast varies from high to low. Participants read the letters, starting with the highest contrast, until they are unable to read 2 or 3 letters in a single group. Each eye is assigned a score based on the contrast of the last group in which 2 or 3 letters were correctly read, ranging from 0 to 2.2 "log of contrast sensitivity" (LogCS) units. A score of 2.0 LogCS, represents a normal sensitivity contrast, and indicates the eye was able to detect 2 of the 3 letters with a contrast of 1 percent (contrast sensitivity = 100 percent or log 2). Scores less than 2.0 signify poorer contrast sensitivity. Pelli-Robson contrast sensitivity score of less than 1.5 is consistent with visual impairment and a score of less than 1.0 represents in visual disability. A positive change from baseline indicates improvement in symptoms.

Measure: Change From Baseline in Contrast Sensitivity at Week 48 and Week 96

Time: Baseline and Week 48; Baseline and Week 96

Description: The assessment of color vision was measured using the Farnsworth-Munsell 100-Hue Color Test. Each of the 4 trays consisted of 21 caps. Participants were asked to sort the randomly arranged caps following the hue order from the first to the last fixed caps. The total error score (TES) was derived by the frequency the caps were misplaced and the severity, or distance of the misplacement. Errors were made whenever caps were misplaced from the correct order. Error scores were calculated according to the distance between any two caps. The error score for each individual cap was the sum of the difference between the number of that cap and the numbers of the cap adjacent to it, minus 2. TES was the total sum of the error scores of the entire set of caps. The best possible score was 0 and there is no defined upper limit to the total error score range. A lower score indicates improved color discrimination ability. A negative change from baseline indicates an improvement in symptoms.

Measure: Change From Baseline in Color Vision

Time: Baseline and Week 48; Baseline and Week 96

6 External Natural History Controlled, Open-Label Intervention Study to Assess the Efficacy and Safety of Long-Term Treatment With Raxone® in Leber's Hereditary Optic Neuropathy (LHON)

LEROS is an open-label interventional Phase IV study, designed to further assess the efficacy and safety of Raxone® in the long-term treatment of LHON patients.

NCT02774005 Leber's Hereditary Optic Neuropathy (LHON) Drug: Idebenone
MeSH: Optic Nerve Diseases Optic Atrophy, Hereditary, Leber
HPO: Leber optic atrophy

Inclusion Criteria: 1. Impaired visual acuity in affected eyes due to LHON 2. No explanation for visual loss besides LHON 3. Age more or equal 12 years 4. Onset of symptoms ≤5 years of Baseline 5. Confirmation of either G11778A, G3460A or T14484C LHON mtDNA (for the ITT population, not required for enrolment) 6. Written informed consent obtained from the patient 7. Ability and willingness to comply with study procedures and visits 8. Women of Childbearing Potential (WCBP) who have a negative urine or serum pregnancy test at Baseline visit and who are willing to use a highly effective contraceptive measure and maintain it until treatment discontinuation. --- G11778A ---

8. Women who are pregnant or have a positive pregnancy test at Baseline visit 9. Women who are breastfeeding Inclusion Criteria: 1. Impaired visual acuity in affected eyes due to LHON 2. No explanation for visual loss besides LHON 3. Age more or equal 12 years 4. Onset of symptoms ≤5 years of Baseline 5. Confirmation of either G11778A, G3460A or T14484C LHON mtDNA (for the ITT population, not required for enrolment) 6. Written informed consent obtained from the patient 7. Ability and willingness to comply with study procedures and visits 8. Women of Childbearing Potential (WCBP) who have a negative urine or serum pregnancy test at Baseline visit and who are willing to use a highly effective contraceptive measure and maintain it until treatment discontinuation. --- G11778A ---

Primary Outcomes

Description: Proportion of eyes with clinically relevant recovery of visual acuity (VA) from Baseline or in which Baseline VA better than 1.0 logMAR was maintained at Month 12 in patients treated with Raxone® ≤1 year after the onset of symptoms, compared to matching external natural history control group

Measure: Proportion of eyes with clinically relevant recovery of visual acuity from Baseline

Time: 12 months

7 Historical Case Record Survey of Visual Acuity Data From Patients With Leber's Hereditary Optic Neuropathy (LHON)

The purpose of this survey is to collect visual acuity data from patients with LHON in order to establish the clinical course (natural history) and visual acuity outcomes in patients with a genetically confirmed diagnosis of LHON. In addition, this survey will generate data that will serve as comparator for the open-label study SNT-IV-006.

NCT02796274 Leber's Hereditary Optic Neuropathy (LHON)
MeSH: Optic Nerve Diseases Optic Atrophy, Hereditary, Leber
HPO: Leber optic atrophy

Clinically Relevant Recovery (CRR) is defined as a VA improvement from off-chart (ETDRS) to 5 letters on-chart, or an on-chart improvement of 10 letters.. Inclusion Criteria: 1. age ≥ 12 years 2. the onset of symptoms is dated after 1999 and is well documented (at least month of onset of symptoms is known for each eye) 3. at least two VA assessments are available within 5 years of onset of symptoms and prior to idebenone use 4. have a genetic diagnosis for LHON for one of the following mitochondrial DNA (mtDNA) mutations: G11778A, G3460A, T14484C Exclusion Criteria: 1. any participation in an interventional clinical trial after the onset of symptoms 2. any other cause of visual impairment (e.g. --- G11778A ---

glaucoma, diabetic retinopathy, AIDS related visual impairment, cataract, macular degeneration, etc.) or any active ocular disorder (uveitis, infections, inflammatory retinal disease, thyroid eye disease, etc.) during the data collection period Inclusion Criteria: 1. age ≥ 12 years 2. the onset of symptoms is dated after 1999 and is well documented (at least month of onset of symptoms is known for each eye) 3. at least two VA assessments are available within 5 years of onset of symptoms and prior to idebenone use 4. have a genetic diagnosis for LHON for one of the following mitochondrial DNA (mtDNA) mutations: G11778A, G3460A, T14484C Exclusion Criteria: 1. any participation in an interventional clinical trial after the onset of symptoms 2. any other cause of visual impairment (e.g. --- G11778A ---

Primary Outcomes

Description: Clinically Relevant Recovery (CRR) is defined as a VA improvement from off-chart (ETDRS) to 5 letters on-chart, or an on-chart improvement of 10 letters.

Measure: In Eyes With VA Assessment Made ≤1 Year After Onset of Symptoms: Proportion of Eyes With Clinically Relevant Recovery (CRR) of VA (Measured by Change in ETDRS Letters) From Baseline (BL) or in Which BL VA Better Than 1.0 logMAR Was Maintained at 12 Months

Time: 12 months

8 Safety and Efficacy Study of Gene Therapy for The Treatment of Leber's Hereditary Optic Neuropathy

This study is meant to evaluate the safety and efficacy of rAAV2-ND4 treatment for Leber hereditary optic neuropathy with the G11778A mutation in mitochondrial DNA.

NCT03153293 Leber Hereditary Optic Neuropathy Drug: rAAV2-ND4
MeSH: Optic Nerve Diseases Optic Atrophy, Hereditary, Leber
HPO: Leber optic atrophy

Safety and Efficacy Study of Gene Therapy for The Treatment of Leber's Hereditary Optic Neuropathy This study is meant to evaluate the safety and efficacy of rAAV2-ND4 treatment for Leber hereditary optic neuropathy with the G11778A mutation in mitochondrial DNA. --- G11778A ---

This is a multi - center , prospective study of 142 patients with the G11778A mutation in Mt-DNA . --- G11778A ---

Primary Outcomes

Description: The Best Corrected Visual Acuity

Measure: BCVA

Time: Change from Baseline at 12 months .

Measure: Computerized Visual Field

Time: Change from Baseline at 12 months .

Secondary Outcomes

Description: visual evoked potential

Measure: VEP

Time: Change from Baseline at 12 months .

Description: retinal nerve fiber layer

Measure: RNFL

Time: Change from Baseline at 12 months .

Measure: Liver function in plasma

Time: Change from Baseline at 12 months .

Measure: kidney function in plasma

Time: Change from Baseline at 12 months .

9 Efficacy and Safety of Bilateral Intravitreal Injection of GS010: A Randomized, Double-Masked, Placebo-Controlled Trial in Subjects Affected With G11778A ND4 Leber Hereditary Optic Neuropathy for Up to One Year

The goal of this clinical trial is to assess the safety and efficacy of GS010, a gene therapy, in improving the retina functional & structural outcomes in subjects with LHON due to the G11778A ND4 mitochondrial mutation when vision loss duration is present up to one year.

NCT03293524 Leber Hereditary Optic Neuropathy Genetic: GS010 Drug: Placebo
MeSH: Optic Nerve Diseases Optic Atrophy, Hereditary Optic Atrophy, Hereditary, Leber
HPO: Leber optic atrophy

Efficacy and Safety of Bilateral Intravitreal Injection of GS010: A Randomized, Double-Masked, Placebo-Controlled Trial in Subjects Affected With G11778A ND4 Leber Hereditary Optic Neuropathy for Up to One Year. --- G11778A ---

Efficacy & Safety Study of Bilateral IVT Injection of GS010 in LHON Subjects Due to the ND4 Mutation for up to 1 Year The goal of this clinical trial is to assess the safety and efficacy of GS010, a gene therapy, in improving the retina functional & structural outcomes in subjects with LHON due to the G11778A ND4 mitochondrial mutation when vision loss duration is present up to one year. --- G11778A ---

- Presence of known/documented mutations, other than the G11778A ND4 LHON-causing mutation, which are known to cause pathology of the optic nerve, retina or afferent visual system. --- G11778A ---

- Documented results of genotyping showing the presence of the G11778A mutation in the ND4 gene and the absence of the other primary LHON-associated mutations (ND1 or ND6) in the subject's mitochondrial DNA. --- G11778A ---

Primary Outcomes

Description: The primary endpoint will be the BCVA reported with LogMAR at 1-Year post-treatment in second affected/not yet affected eyes. The change from baseline in second affected/not yet affected eyes receiving GS010 and placebo will be the primary response of interest. LogMAR BCVA will be used for statistical purposes.

Measure: Best-Corrected Visual Acuity (BCVA) reported using Log of the Minimal Angle of Resolution (LogMAR) - 1 year

Time: at 1-Year post baseline treatment

Secondary Outcomes

Description: LogMAR BCVA at each timepoint of the follow-up period and at 2-years post-treatment, for second affected/not yet affected eyes receiving GS010 versus placebo and also for first affected eyes receiving GS010. The change from baseline of the LogMAR BCVA will be used for statistical analyses.

Measure: Best-Corrected Visual Acuity (BCVA) reported with LogMAR - 2 years

Time: at 2-Years post baseline treatment

Description: Response status over time and at 1 and 2-years post baseline treatment. Response status will be assessed for second affected/not yet affected eyes receiving GS010 versus placebo and also for first affected eyes receiving GS010. Definitions of responder eyes include: Eyes whose LogMAR BCVA improves (i.e. decreases) by ≥ 0.3 LogMAR (equivalent to a gain of ≥ 15 ETDRS letters) compared to baseline. Eyes whose LogMAR BCVA does not increase (i.e. worsen) by ≥ 0.3 LogMAR (equivalent to eye that lose ≤ 15 ETDRS letters) compared to baseline. Eyes whose LogMAR visual acuity is < 1.0 (i.e. better than LogMAR 1.0, equivalent to better than Snellen acuity of 20/200).

Measure: Responder Analysis

Time: at 1-Year and 2-Years post baseline treatment

Description: Parameters measured with SD-OCT over time and at 1 and 2-years post baseline treatment. The change from baseline will be the response. Analysis will be performed mainly for second affected/not yet affected eyes treated with GS010 versus placebo and also for first affected eyes receiving GS010 as well

Measure: Spectral-Domain - Optical Coherence Tomography (SD-OCT) parameter

Time: at 1-Year and 2-Years post baseline treatment

Description: Parameters measured with HVF 30-2 over time and at 1 and 2-years post baseline treatment. The change from baseline will be the response. Analysis will be performed mainly for second affected/not yet affected eyes treated with GS010 versus placebo and also for first affected eyes receiving GS010 as well

Measure: Humphrey Visual Field (HVF) parameter

Time: at 1-Year and 2-Years post baseline treatment

Description: Parameters measured with Pelli Robson Low Vision Contrast Sensitivity over time and at 1 and 2-years post baseline treatment. The change from baseline will be the response. Analysis will be performed mainly for second affected/not yet affected eyes treated with GS010 versus placebo and also for first affected eyes receiving GS010 as well

Measure: Pelli Robson Low Vision Contrast Sensitivity parameter

Time: at 1-Year and 2-Years post baseline treatment

Description: Visual Functioning Questionnaire-25 at 1 and 2-years post-treatment

Measure: Quality of Life: Visual Functioning Questionnaire-25

Time: at 1-Year and 2-Years post baseline treatment

Description: 36-Item Short Form Health Survey, version 2 Questionnaire at 1 and 2-years post-treatment.

Measure: Quality of Life: 36-Item Short Form Health Survey, version 2 Questionnaire

Time: at 1-Year and 2-Years post baseline treatment

Other Outcomes

Description: Adverse events (AEs) and serious adverse events (SAEs), including those that are treatment-emergent and non-treatment-emergent, throughout the study period and at each study visit. Incidence and severity of systemic and local (ocular) AEs and SAEs will be determined at each clinical site and for the entire study cohort.

Measure: Adverse events (AEs) and serious adverse events (SAEs)

Time: up to 2-Years post baseline treatment

Description: Results of physical examinations

Measure: Physical examinations

Time: At 2-Years post baseline treatment

Description: Results of Electrocardiograms (ECGs)

Measure: Electrocardiograms

Time: At 2-Years post baseline treatment

Description: Results of laboratory tests from blood collection

Measure: Laboratory results

Time: At 2-Years post baseline treatment

Description: Results of immune response evaluations Time course of the humoral immune response measured with Neutralizing Antibodies (Nab) against Adeno-associated virus vector 2 (AAV2) Time course of the cellular immune response against AAV2

Measure: Immune response evaluations

Time: Up to 2-Years post baseline treatment

Description: Results of bio-dissemination testing up to 4-weeks post-treatment

Measure: Blood Bio-dissemination of AAV2 Vector DNA

Time: up to 4 weeks post-treatment

10 Long-term Follow-up of ND4 LHON Subjects Treated With GS010 Ocular Gene Therapy in the RESCUE or REVERSE Phase III Clinical Trials

The goal of this clinical trial is to assess the long-term safety and efficacy of GS010, a gene therapy, and assess the quality of life in subjects with LHON due to the G11778A ND4 mitochondrial mutation and who were treated in the Rescue or Reverse studies.

NCT03406104 Leber Hereditary Optic Neuropathy (Optic, Atrophy, Hereditary, Leber) Genetic: GS010 Other: Sham Intravitreal Injection
MeSH: Optic Nerve Diseases Optic Atrophy, Hereditary, Leber Atrophy
HPO: Leber optic atrophy

RESCUE and REVERSE Long-term Follow-up The goal of this clinical trial is to assess the long-term safety and efficacy of GS010, a gene therapy, and assess the quality of life in subjects with LHON due to the G11778A ND4 mitochondrial mutation and who were treated in the Rescue or Reverse studies. --- G11778A ---

Primary Outcomes

Description: AEs or SAEs (ocular or systemic) related to IMP or administration procedure, as judged by the Investigator, reported during the long-term follow-up visits (2, 2.5, 3, 4, and 5 years) from the period of 96 weeks up to 5 years post-treatment and summarized descriptively by type, frequency (number, percentage), severity, causal relationship, and seriousness

Measure: Adverse events (AEs) or serious adverse events (SAEs) (ocular or systemic)

Time: Up to 5-Year post-treatment

Secondary Outcomes

Description: Change in best BCVA reported with LogMAR

Measure: Best-Corrected Visual Acuity (BCVA) reported with LogMAR

Time: Up to 5-Year post-treatment

Description: Change of parameters measured with HVF 30-2

Measure: HumphreyTM visual field (HVF) 30-2 parameters

Time: Up to 5-Year post-treatment

Description: Change of parameters measured with SD-OCT

Measure: Spectral domain optical coherence tomography (SD-OCT) parameters

Time: Up to 5-Year post-treatment

Description: Response status of eyes treated with GS010 IVT injection compared to eyes treated with sham IVT injection (An improvement of at least 15 ETDRS letters/Eyes that lose less than the 15 ETDRS letters)

Measure: Responder Analysis

Time: Up to 5-Year post-treatment

Description: Time course of the response in eyes treated with GS010 IVT injection compared to eyes treated with sham IVT injection, for the BCVA reported with LogMAR, for parameters measured with HVF 30-2 and SD-OCT

Measure: Time course of the response

Time: Up to 5-Year post-treatment

Description: Visual improvement as measured by LogMAR by analysis of covariance (ANCOVA)

Measure: Visual improvement

Time: Up to 5-Year post-treatment

Description: Change of GCL thickness/volume and topographical map and other parameters measured by SD-OCT using a mixed model of ANCOVA

Measure: Change of ganglion cell layer (GCL) thickness/volume and topographical map and other parameters measured by SD-OCT

Time: Up to 5-Year post-treatment

Description: QOL as measured with VFQ-25 subject-rated instrument

Measure: Quality of Life: Visual Functioning Questionnaire 25 (VFQ-25)

Time: Up to 5-Year post-treatment

Description: QOL as measured with SF-36v2 subject-rated instrument

Measure: Quality of Life: 36-Item Short Form Health Survey, version 2 (SF-36-v2)

Time: Up to 5-Year post-treatment

11 Efficacy Study of Gene Therapy for The Treatment of Acute LHON Onset Within Three Months

Efficacy Study of Gene Therapy for The Treatment of Acute Leber's Hereditary Optic Neuropathy (LHON) onset within three months

NCT03428178 Acute LHON Onset Within Three Months Onset Between 3 to 6 Months Onset Between 6 to 12 Months Onset Between 12 to 24 Months Onset Between 24 to 60 Months Onset Over 60 Months Drug: rAAV2-ND4
MeSH: Optic Atrophy, Hereditary, Leber
HPO: Leber optic atrophy

This is a multi - center , prospective study of 120 patients with the G11778A mutation in Mt-DNA.This clinical trial recruited 20 patients with the 11778 mutation of MT-DNA onset within three months,20 between 3 to 6 months,20 between 6 to 12 months,20 between 12 to 24 months,20 between 24 to 60 months,and 20 over 60 months.. --- G11778A ---

Primary Outcomes

Description: The Best Corrected Visual Acuity

Measure: BCVA

Time: Change from Baseline at 12 months

Secondary Outcomes

Description: Visual Field index

Measure: Computerized Visual Field

Time: Change from Baseline at 12 months

Description: Mean Defect

Measure: Computerized Visual Field

Time: Change from Baseline at 12 months

Description: visual evoked potential

Measure: VEP

Time: Change from Baseline at 12 months

Description: retinal nerve fiber layer

Measure: RNFL

Time: Change from Baseline at 12 months

Description: Before and after the treatment,Liver function in plasma will be checked.

Measure: Liver function in plasma

Time: Before treatment and in the first ,third,sixth,twelfth month after the treatment

Description: Before and after the treatment,kidney function in plasma will be checked.

Measure: kidney function in plasma

Time: Before treatment and in the first ,third,sixth,twelfth month after the treatment

12 EAP Single Patient: Safety of Bilateral Intravitreal Injection of GS010 in a Single Subject Affected With G11778A ND4 Leber Hereditary Optic Neuropathy

Expanded Access Use for a single patient of Bilateral Intravitreal Injection of GS010 in a Single Subject Affected with G11778A ND4 Leber Hereditary Optic Neuropathy

NCT03672968 Leber Hereditary Optic Neuropathy (Optic, Atrophy, Hereditary, Leber) Genetic: GS010
MeSH: Optic Nerve Diseases Optic Atrophy, Hereditary, Leber Atrophy
HPO: Leber optic atrophy

EAP Single Patient: Safety of Bilateral Intravitreal Injection of GS010 in a Single Subject Affected With G11778A ND4 Leber Hereditary Optic Neuropathy. --- G11778A ---

EAP_GS010_single Patient Expanded Access Use for a single patient of Bilateral Intravitreal Injection of GS010 in a Single Subject Affected with G11778A ND4 Leber Hereditary Optic Neuropathy The EAP applies to patients not eligible to ongoing GS010 clinical trials. --- G11778A ---

Inclusion Criteria: - Presence of documented G11778A ND4 LHON-causing mutation - Signature of informed consent and assent from the parent/guardian and the patient. --- G11778A ---

- Presence of known/documented mutations, other than the G11778A ND4 LHON-causing mutation, which are known to cause pathology of the optic nerve, retina or afferent visual system. --- G11778A ---



HPO Nodes


Leber optic atrophy
Genes 11
ND2 ATP6 ND4L ND5 CYTB ND1 TBC1D24 ND4 CPLX1 ND6 COX3
Polyneuropathy
Genes 59
GCLC NAGS SLC12A6 ERCC6 AIFM1 C12ORF65 PSAP CYP7B1 COX3 PEX11B ATP6 ARL6IP1 COQ7 OPA1 PIK3R5 SH3TC2 LDB3 PEX12 ALAD ABHD12 FAM126A EDNRB NGLY1 ND2 ABCD1 CYTB PEX7 RPIA GSN TBC1D24 GRM1 SNAP29 TTR ND5 PDK3 ND4 GSN DGUOK PMM2 ND4L DHH ND1 TTR SEPTIN9 FUCA1 DARS2 PRPS1 SETX SLC25A19 PDYN ATP7B ERCC8 DHH DMXL2 MYOT MYD88 ARL6IP1 CD59 ND6